Imaging the Mechanics and Electromechanics of the Heart

Abstract-The heart is a mechanical pump that is electrically driven. We have previously shown that the contractility of the cardiac muscle can reliably be used in order to assess the extent of ischemia using myocardial elastography. Myocardial elastography estimates displacement and strain during the natural contraction of the myocardium using signal processing techniques on echocardiograms in order to assess the change in mechanical properties as a result of disease. In this paper, we showed that elastographic techniques can be used to estimate and image both the mechanics and electromechanics of normal and pathological hearts in vivo. In order to image the mechanics throughout the entire cardiac cycle, the minimum frame rate was determined to be on the order of 150 fps in a long-axis view and 300 fps in a short-axis view. The incremental and cumulative displacement and strains were measured and imaged for the characterization of normal function and differentiation from infracted myocardium. In order to image the electromechanical function, the incremental displacement was imaged in consecutive cardiac cycles during end-systole in both dogs and humans. The contraction wave velocity in normal dogs was found to be twice higher than in normal humans and twice lower than in ischemic dogs. In conclusion, we have demonstrated that elastographic techniques can be used to detect and quantify the mechanics and electromechanics of the myocardium in vivo. Ongoing investigations entail assessment of myocardial elastography in characterizing and quantifying ischemia and infarction in vivo

Furin Prodomain ppFurin Enhances Ca2+ Entry Through Orai and TRPC6 Channels’ Activation in Breast Cancer Cells

The intracellular calcium concentration ([Ca2+]i) modulation plays a key role in the regulation of cellular growth and survival in normal cells and failure of [Ca2+]i homeostasis is involved in tumor initiation and progression. Here we showed that inhibition of Furin by its naturally occurring inhibitor the prodomain ppFurin in the MDA-MB-231 breast cancer cells resulted in enhanced store-operated calcium entry (SOCE) and reduced the cell malignant phenotype. Expression of ppFurin in a stable manner in MDA-MB-231 and the melanoma MDA-MB-435 cell lines inhibits Furin activity as assessed by in vitro digestion assays. Accordingly, cell transfection experiments revealed that the ppFurin-expressing cells are unable to adequately process the proprotein convertase (PC) substrates vascular endothelial growth factor C (proVEGF-C) and insulin-like growth factor-1 receptor (proIGF-1R). Compared to MDA-MB-435 cells, expression of ppFurin in MDA-MB-231 and BT20 cells significantly enhanced SOCE and induced constitutive Ca2+ entry. The enhanced SOCE is impaired by inhibition of Orai channels while the constitutive Ca2+ entry is attenuated by silencing or inhibition of TRPC6 or inhibition of Orai channels. Analysis of TRPC6 activation revealed its upregulated tyrosine phosphorylation in ppFurin-expressing MDA-MB-231 cells. In addition, while ppFurin had no effect on MDA-MB-435 cell viability, in MDA-MB-231 cells ppFurin expression reduced their viability and ability to migrate and enhanced their sensitization to the apoptosis inducer hydrogen peroxide and similar results were observed in BT20 cells. These findings suggest that Furin inhibition by ppFurin may be a useful strategy to interfere with Ca2+ mobilization, leading to breast cancer cells’ malignant phenotype repression and reduction of their resistance to treatments.This research was funded by SIRIC-Brio, La Ligue Contre le Cancer and Region Nouvelle Aquitaine to A.M.K. and by PID2019-104084GB-C21 and PID2019-104084GB-C22/AEI/10.13039/501100011033, MICINN (Grant BFU2016-74932-C2) and Junta de Extremadura-Fondo Europeo de Desarrollo Regional (FEDER; Grants IB16046 and GR18061) to J.A.R. and T.S. J.J.L. is supported by a contract from Junta de Extremadura (TA18011). C.C. is supported by a contract from Junta de Extremadura—FEDER

Role of Furin in Colon Cancer Stem Cells Malignant Phenotype and Expression of LGR5 and NANOG in KRAS and BRAF-Mutated Colon Tumors

Proprotein convertases or PCs are known to regulate the malignant phenotype of colon cancer cells by different mechanisms, but their effects on cancer stem cells (CSCs) have been less widely investigated. Here, we report that PCs expression is altered in colon CSCs, and the inhibition of their activity reduced colon CSCs growth, survival, and invasion in three-dimensional spheroid cultures. In vivo, repression of PCs activity by the general PC inhibitors α1-PDX, Spn4A, or decanoyl-RVKR-chloromethylketone (CMK) significantly reduced tumor expression levels of the stem cell markers LGR5 and NANOG that are associated with reduced tumor xenografts. Further analysis revealed that reduced tumor growth mediated by specific silencing of the convertase Furin in KRAS or BRAF mutated-induced colon tumors was associated with reduced expression of LGR5 and NANOG compared to wild-type KRAS and BRAF tumors. Analysis of various calcium regulator molecules revealed that while the calcium-transporting ATPase 4 (ATP2B4) is downregulated in all the Furin-silenced colon cancer cells, the Ca2+-mobilizing P2Y receptors, was specifically repressed in BRAF mutated cells and ORAI1 and CACNA1H in KRAS mutated cells. Taken together, our findings indicate that PCs play an important role in the malignant phenotype of colon CSCs and stem cell markers’ expression and highlight PCs repression, particularly of Furin, to target colon tumors with KRAS or BRAF mutation.This research was funded by La Region Nouvelle Aquitaine, Siric Brio, Ligue Contre le Cancer, Planete Vegetal and INSERM. M.J.A.-B. was supported by a grant PID2020-119715GB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”, and by the European Union H2020-FETOPEN Project 899417 Circular Vision

Absorbing boundary conditions for the Westervelt equation

The focus of this work is on the construction of a family of nonlinear absorbing boundary conditions for the Westervelt equation in one and two space dimensions. The principal ingredient used in the design of such conditions is pseudo-differential calculus. This approach enables to develop high order boundary conditions in a consistent way which are typically more accurate than their low order analogs. Under the hypothesis of small initial data, we establish local well-posedness for the Westervelt equation with the absorbing boundary conditions. The performed numerical experiments illustrate the efficiency of the proposed boundary conditions for different regimes of wave propagation

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Calibration of the CMS Drift Tube Chambers and Measurement of the Drift Velocity with Cosmic Rays

Peer reviewe

CMS Data Processing Workflows during an Extended Cosmic Ray Run

Peer reviewe

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Aligning the CMS Muon Chambers with the Muon Alignment System during an Extended Cosmic Ray Run

Peer reviewe